System comprising a pre-fillable syringe and a package for the pre-fillable syringe

ABSTRACT

System comprising a pre-fillable syringe with a syringe barrel and a syringe tip and a package suitable and intended for receiving the pre-fillable syringe, wherein the syringe tip is provided with a tip cap, wherein the system comprises a replacement cap for the pre-fillable syringe, wherein the package is suitable and intended for receiving the replacement cap.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part (CIP) of applicationSer. No. 16/355,343, filed Mar. 15, 2019, the entire contents anddisclosure of which are hereby incorporated by reference in theirentirety into the present application.

TECHNICAL FIELD

The invention relates to a package suitable and intended for receiving apre-fillable syringe comprising a syringe barrel and a syringe tip,wherein the syringe tip is provided with a tip cap. The invention alsorelates to a system and the use of the system comprising a pre-fillablesyringe with a syringe barrel and a syringe tip and a package suitableand intended for receiving the pre-fillable syringe, wherein the syringetip is provided with a tip cap. Further, the invention relates to areplacement cap for a pre-fillable syringe.

BACKGROUND

Pre-fillable syringes can be used as a kit together with the medium tobe administered or delivered to the user, where the pre-fillablesyringes of the kit are filled with the medium.

In particular, nowadays, pre-filled syringes have emerged as one of thefastest-growing choices for unit dose medication. The handling of suchsyringes is easy because the medium to administer does not need to betransferred to the syringe before the usage. The usage of pre-filledsyringes minimizes drug waste and increases product life span.

The administration of drugs to patients, other than by an injection, hasbecome more popular, due to the development of new drugs. Possible waysof administration are, in particular, oral, intranasal, topic, dermaland further external applications. For such applications, pre-filledsyringes may be the best way to store, transport and administer thedrugs.

Also, for mediums or drugs which are injected in the body, pre-filledsyringes are a convenient choice. In particular, modern vaccines reactvery sensibly to outer influence factors and are therefore securelystored in a pre-filled syringe.

Pre-fillable syringe bodies comprise a syringe barrel, a syringe tip andoptionally a finger flange. In some cases, the syringe tip is alreadyprovided with a piercing means. A piercing means may be a needle, acanula, or a similar element.

The syringe bodies are produced by a primary packaging producer underclean room conditions. After a sterilization, the syringe bodies areprovided with a tip cap and placed in a so-called syringe nest. The tipcap usually is placed on the syringe tip and may also enclose a needlearranged in the syringe tip.

The pre-fillable syringe is then delivered to a pharmaceutical companywhich either provide a kit together with the medium to administer or,preferably, fills the syringes with the medium.

In the latter case, after the filling process, a plunger or piston isintroduced in the syringe barrel, by which the barrel is closed on itsproximal side. The filled syringe is then placed in a secondarypackaging.

The tip cap can seal the tip and optionally the needle. Usually, the tipcaps are at least partially made of an elastic material. Due to thelimited space for a syringe in the syringe nest, the tip caps areusually designed as small as possible. Such small sized tip caps may be,however, inconvenient for the user to handle.

In some cases, the user needs to set the dosage before the actualadministration of the medium, which may be done at a later point. Forthis purpose, the tip cap may need to be temporally removed. Thereclosing of the syringe with the tip cap may result in an unwantedintroduction of a portion of air in the syringe barrel. Such a portionof air may cause irritations to the patient. In cases where the mediumin the syringe barrel is a higher-viscosity medium, the enclosed portionof air may be difficult to remove.

WO 2018/038078 A1 discloses a medical equipment package with a pluralityof syringe packaging bodies including a prefilled syringe system and apackaging main body, and an outer box which accommodates a plurality ofsyringe packaging bodies. A needle unit of the prefilled syringe systemis supported with respect to a needle unit case with a largest outerdiameter portion provided at a tip end of a needle hub engaging with aninner surface of the needle unit case. In the outer box, a plurality ofsyringe packaging bodies is arranged such that an axial direction of aneedle body is in an up-and-down direction of the outer box. Theprefilled syringe is sealed with a sealing cap, however no replacementcap is provided.

SUMMARY

An object of the invention is therefore to provide a pre-fillablesyringe, package for receiving a pre-fillable syringe, and a systemcomprising a pre-fillable syringe and a package that overcomes theabove-mentioned disadvantages.

The invention is also directed to the system of the invention, whereinthe syringe is pre-filled with a ready-to-use pharmaceuticalformulation.

Furthermore, the invention is directed to a kit comprising the system ofthe invention together with a pharmaceutical formulation in the form ofeither a ready-to-use aqueous solution or a powder to be reconstitutedin a suitable vehicle, and instructions to administer saidpharmaceutical formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a pre-fillable syringe without a tip cap;

FIG. 2a shows a pre-fillable syringe with a tip cap;

FIG. 2b shows a replacement cap;

FIG. 3 shows a pre-fillable syringe with a replacement cap;

FIG. 4 shows a pre-fillable syringe with a replacement cap on a supportsurface;

FIG. 5a shows a pre-fillable syringe with a tip cap, as in FIG. 2 a;

FIG. 5b shows a replacement cap as in FIG. 2b , with different footportion;

FIG. 6 shows a package body according to one embodiment without apre-fillable syringe;

FIG. 7 shows a package body according to one embodiment with apre-fillable syringe and a replacement cap;

FIG. 8 shows a package body according to one embodiment with apre-fillable syringe placed in a replacement cap;

FIG. 9a shows a bottom perspective view of a plunger according to one ormore embodiments;

FIG. 9b shows a top perspective view of the plunger;

FIG. 9c shows a side view of the plunger;

FIG. 9d shows a bottom plan view of the plunger; and

FIG. 9e shows a top plan view of the plunger.

LIST OF REFERENCE NUMERALS

1 package;

2 first receiving element;

3 package body;

4 first cavity of the package body;

5 sidewall of the package body;

6 bottom wall of the package body;

7 second receiving element;

7 a first of the second receiving elements;

7 b second of the second receiving elements;

8 third receiving element;

8 a, 8 b walls of the third receiving element ;

12 sidewall of the first receiving element;

13 height of the sidewall;

15 closure element;

26 semicircular top section of the second receiving element;

27 base section of the second receiving element;

30 fixture element;

31 flange;

100 pre-fillable syringe;

101 syringe barrel;

101 a distal end of the syringe barrel

101 b proximal end of the syringe barrel

102 syringe tip;

102 a outer diameter of the syringe tip;

103 tip cap;

103 a outer diameter of the tip cap;

103 b distal end face of the tip cap;

104 rod;

105 finger flange;

106 length of the pre-fillable syringe;

107 width of the finger flange;

108 width of the syringe barrel;

109 finger support;

110 region where the syringe barrel merges into the syringe tip;

111 central axis of the pre-fillable syringe;

112 radius of the syringe barrel;

200 system;

300 replacement cap;

301 inner cap;

302 outer collar;

303 foot portion;

304 opening of the inner cap;

305 ring;

306 struts;

307 center axis of the replacement cap;

308 edge distance;

309 opening of the replacement cap;

309 a opening area of the replacement cap;

310 height;

311 bearing area;

312 distal end face of the foot portion;

313 edge of the bearing area;

314 cut portion;

400 support surface;

500 plunger;

502 bottom of plunger;

X longitudinal axis of the package body;

Y horizontal axis of the package body;

Z vertical axis of the package body;

X′ longitudinal axis of the pre-fillable syringe;

Y′ horizontal axis of the pre-fillable syringe;

Z′ vertical axis of the pre-fillable syringe;

X″ longitudinal axis of the replacement cap;

Y″ horizontal axis of the replacement cap;

Z″ vertical axis of the replacement cap;

X′ 1 distal direction

X′2 proximal direction;

L2 height of the central axis of the syringe above the bottom wall; and

L4 height of the sidewall of the package body.

DETAILED DESCRIPTION

The problem is addressed by a system, comprising a pre-fillable syringewith a syringe barrel and a syringe tip and a package suitable andintended for receiving the pre-fillable syringe, wherein the syringe tipis provided with a tip cap, wherein the system comprises a replacementcap for the pre-fillable syringe, and wherein the package is suitableand intended for receiving the replacement cap.

The system has the advantage that a package, presented to the user,comprises the pre-fillable syringe to use and a suitable replacementcap. The user may retrieve the pre-fillable syringe from the package,remove the tip cap and optionally set the dosage of the pre-fillablesyringe. The replacement cap is already available to the user and doesnot need to be obtained otherwise. Further, the replacement cap does notneed to be retrieved from an additional package. For such a retrieval ofthe replacement cap from the additional package, the user needs to putthe possibly already open syringe down. Putting down the pre-fillablesyringe could contaminate the syringe tip and implies an unnecessarycomplicated handling.

On the contrary, the system according to this invention provides theuser the pre-fillable syringe and the replacement cap in one package.The replacement cap is therefore always available with the pre-fillablesyringe and does not need to be obtained at a time, when the tip cap ispossibly already removed. The mounting of the replacement cap maytherefore be performed in an uncomplicated manner.

The further use of a replacement cap also has the advantage that thehandling of the syringe is easier for the user, since it may bedifficult to grasp and remove the comparatively small tip cap.

In the following, the expressions “distal” and “proximal” are understoodsuch that a distal end of a syringe is closer to the application site asthe proximal end. The expressions “distal direction” and “proximaldirected” are understood analogously.

In the following, the longitudinal axis (X), horizontal axis (Y), andvertical axis (Z) are used in relation to the package body. Thelongitudinal axis (X′), horizontal axis (Y′), and vertical axis (Z′) areused in relation to the pre-fillable syringe. The longitudinal axis(X″), horizontal axis (Y″), and vertical axis (Z″) are used in relationto the replacement cap.

According to a preferred embodiment, the package comprises a packagebody forming a first cavity defined by a sidewall and a bottom wall.Preferably, the pre-fillable syringe is arrangeable in said firstcavity. Preferably, the package body extends along a longitudinal axis(X), a horizontal axis (Y) and a vertical axis (Z), which areperpendicular to each other.

According to a preferred embodiment, at least one second receivingelement is provided in the first cavity of the package body, in whichthe syringe barrel is receivable. Preferably two second receivingelements are provided in the first cavity of the package body.Preferably, the at least one second receiving element is arranged on thebottom wall. It is further advantageous that the at least one secondreceiving element comprises a semicircular top section, arranged on abase section. The semicircular top section extends preferably along thehorizontal axis (Y) and the longitudinal axis (X) and is open in thevertical axis (Z). Further, the semicircular top section is suitable andintended for receiving the syringe barrel. The semicircular top sectioncomprises two arms which encompass the syringe barrel at least in part.

According to a further preferred embodiment a distal end of the syringebarrel is supported by a first of the second receiving elements and aproximal end of the syringe barrel is supported by a second of thesecond receiving elements. It is advantageous that a first of the secondreceiving elements is located close to or at the region where thesyringe barrel merges into the syringe tip. Further, it is preferredthat the second of the second receiving elements is located close to thefinger flange of the syringe arranged in the package body. Preferablythe first and the second of the second receiving elements are separatedalong the longitudinal axis (X′) of the pre-fillable syringe. Thus, in astate where the pre-fillable syringe is arranged in the package body andthe syringe barrel is received by the preferably two second receivingelements, a central axis of the pre-fillable syringe extends preferablyparallel to the bottom wall of the package body.

Advantageously, the central axis extends in a height L2 above the bottomwall. The height L2 is dimensioned such that an easy grasping of thepre-fillable syringe is possible.

According to a further preferred embodiment, at least one thirdreceiving element is provided in the first cavity of the package body,in which a rod of the pre-fillable syringe is receivable. Preferably,the third receiving element comprises two walls extending along thevertical axis (Z), forming a cavity in which the rod is received.Preferably, said walls extend along the longitudinal axis (X).Advantageously, the at least one third receiving element has a bottomwall which is formed semicircularly and connects said walls with eachother.

It is further advantageous that a gap between the second of the secondreceiving elements and the third receiving element is provided.Preferably a finger flange of the pre-fillable syringe projects throughsaid gap such that the finger flange is sandwiched between second of thesecond receiving elements and the third receiving element. Through thisgap, the finger flange of the pre-fillable syringe may preferablyproject, when the syringe is placed inside the package body. Since thefinger flange is preferably sandwiched between the second of the secondreceiving elements and the third receiving element the pre-fillablesyringe is fasted in the package body due to an engagement of the fingerflange with the second of the second receiving elements and the thirdreceiving element. The length of said walls is essentially determined bythe length of a section of the rod, which projects from the syringebarrel, without the length of the rod in said gap between the second ofthe second receiving elements and the third receiving element.

According to a preferred embodiment, the pre-fillable syringe furthercomprises a plunger or a piston connected to a rod projecting out of thesyringe barrel. Advantageously, the pre-fillable syringe comprises alsoa finger flange. The finger flange may be formed on the syringe barrel.It is also conceivable that a separate finger flange element isconnected to the syringe barrel, which provides a larger grippingsurface. The syringe tip is preferably formed as a cone. Advantageously,the syringe tip has a Luer-Cone. Currently, ISO 80369 governs the Luerstandards. The syringe tip may preferably also be equipped with apiercing means, which may be a needle, a canula, or a similar means.

However, since it is intended for sublingual administration to neonates,preferably the syringe can be used without piercing means on the tip toavoid accidental harm to their mouth.

The pre-fillable syringe is advantageously provided with a tip cap,which is arranged on the syringe tip. The tip cap may consist at leastin part of an elastomeric material. Advantageously, the pre-fillablesyringe may consist of glass or plastics.

According to a preferred embodiment, the replacement cap is arranged inthe package, such that the replacement cap or an opening of thereplacement cap is oriented along a vertical axis (Z) of the packagebody. Preferably, an opening area of the replacement cap is orientedparallel to the bottom wall of the package body. Such an arrangementallows an easy mounting of the replacement cap on the pre-fillablesyringe. The replacement cap does not need to be removed from thepackage for the mounting process. The pre-fillable syringe may beinserted in the replacement cap, while the replacement cap still remainsin the package. Once the replacement cap is mounted on the pre-fillablesyringe, the replacement cap is removed together with the pre-fillablesyringe from the package. This allows a handling of the syringe withonly one hand. Obtaining a separate replacement cap may require atwo-hand operation, since the replacement cap needs to be extracted fromthe separate package and needs to be oriented relative to thepre-fillable syringe, such that a mounting is possible.

According to a preferred embodiment, the replacement cap comprises aninner cap for an engagement with the syringe tip. Advantageously, thereplacement cap comprises an outer collar engaging with the syringebarrel for mounting the replacement cap on the syringe barrel. Further,it is favorable that the replacement cap comprises a foot portion.

The inner cap is preferably arranged on the foot portion of thereplacement cap. Advantageously, the inner cap may consist at leastpartially of an elastomeric material, such that a sealing connectionwith the syringe tip is possible. The syringe tip may preferably beintroduced in the inner cap through an opening of the inner cap.

The outer collar is advantageously formed as a ring which is arrangedalong a longitudinal axis (X″) above the opening of the inner cap. Thering is preferably supported by struts which are arranged at the footportion and surround the inner cap radially. Preferably, the threestruts are placed along the circumference of the ring with an equaldistance to each other. The struts project from the ring radially inwardand abut at the syringe barrel, when the replacement cap is placed onthe pre-fillable syringe.

Preferably, the opening area of the replacement cap is defined by thering and the opening of the inner cap, which is placed along thelongitudinal axis (X″) underneath the opening of the ring. The openingof the ring and the opening are advantageously parallel to each otherand share the same central axis. Preferably, the opening area of thereplacement cap is defined by the ring. The opening area of thereplacement cap, which is preferably defined by the ring, and an openingarea of the inner cap are preferably oriented parallel to the bottomwall of the package body.

According to a preferred embodiment, a first receiving element isprovided in the first cavity of the package body. Preferably, thereplacement cap is received in the first receiving element.Advantageously, the foot portion of the replacement cap is received inthe first receiving element. The replacement cap is therefore placedupright in the package. Thus, the opening area of the replacement cap isdefined by the ring and an opening area of the inner cap are preferablyoriented parallel to the bottom wall of the package body.

According to a preferred embodiment, the foot portion is suitable toprovide a stable upright positioning of the pre-fillable syringe withthe replacement cap on a support surface. Preferably, the foot portioncomprises a bearing area which contacts the support surface. Preferably,the bearing area comprises an edge, which surrounds a center axis of thereplacement cap at an edge-distance.

For a user, an upright positioning represents a very handy, practicalway to place the pre-fillable syringe after removing it from thepackage. Under an upright positioning, a positioning of the distal endof the pre-fillable syringe on a supporting surface, is understood. Sucha positioning bears the advantage that the proximal end is equipped withthe finger flange and the rod is easy to grasp. A pre-fillable syringetypically has an extension which is by far larger along the longitudinalaxis (X′) than along the horizontal axis (Y′).

A stable positioning is possible as long as the center of gravity iswithin an area defined by a tilting edge of the bearing area. Thebearing area may stretch over a part of a distal end face of thereplacement cap, which constitutes the distal end of the foot portion.It is also conceivable that the bearing area stretches over the entiredistal end face. Further, it is conceivable that the bearing areastretches along the edge of the distal end face.

A displacement of the center of gravity in a radial direction may notaffect the stability of the standing, as long as the center of gravityis not further radially outwards placed than the tilting edge. Due tothe provision of a finger flange at the proximal end of the pre-fillablesyringe, the center of gravity is closer to the proximal end of thesyringe. This means that a small displacement of the center of gravitycan cause the upright standing syringe to topple.

Preferably, the edge-distance between the edge of the bearing area andthe center axis is at least twice the radius of the syringe barrel, morepreferably, the edge-distance is at least three times the radius of thesyringe barrel. Preferably, the edge-distance is at least four times theradius of the syringe barrel. Preferably, the edge-distance is at leastfive times the radius of the syringe barrel. Due to such an embodiment,the tilting edge is further away from the center axis. Thus, a largerdisplacement of the center of gravity is possible, before the uprightstanding syringe topples. Hence, the standing stability is enhanced.

Preferably, the distal end face of the foot portion comprises an edge,surrounding a center axis of the replacement cap at a certain distance.This edge may preferably be parallel to the edge of the bearing area,which is considered as a tilting edge. The edge of the distal end facedefines the shape of the foot section, which can be arbitrary.Advantageously, the foot portion has a disc-like shape. Preferably, thefoot portion is essentially circular. Alternatively, the foot portioncan be rectangular.

After the described equipping of the syringe with a replacement cap,which may be done only one-handed, due to the preferable placement andorientation of the replacement cap in the package, the syringe may beplaced standing upright and is easily accessible for the user, whenneeded.

According to a preferred embodiment, the bearing area and/or the edgesurrounding the bearing face is/are coated at least partially with arubberized material. Such an embodiment bears the advantage thatslipping of the foot portion on the supporting surface is inhibited orminimized.

According to a preferred embodiment, the foot portion is designed as asuction cup. A suction cup is a device or object that uses the negativefluid pressure of air to adhere to nonporous surfaces, creating apartial vacuum. The working face of the foot portion is preferably madeof elastic, flexible material and has a curved surface. When the centerof the foot portion is pressed against a flat supporting surface, thevolume of the space between the foot portion and the flat surface isreduced. Thus, the air or water between the foot portion and the surfaceis to be expelled past the edge of the cup. By this, a lack of pressuredevelops between the foot portion and the supporting surface. Thepressure difference between the atmosphere on the outside of the footportion and the low-pressure between the foot portion and the supportingsurface keeps the foot portion adhered to the surface.

Preferably, the replacement cap is produced by injection molding,preferably by multi-component injection molding.

According to a further preferred embodiment, the sidewall of the packagebody extends essentially along a vertical axis (Z). By extendingessentially, it is meant that the sidewall may have a comparativelysmall angle (α) to the vertical axis (Z). Such an angle could be in arange between 0° to 25°, preferably 0° to 10°, preferably 0° to 5°.

Advantageously, the sidewall of the package body is provided with aflange on its upper end, wherein the flange extends outwards essentiallyalong the longitudinal (X) or the horizontal (Y) axis. Preferably, theflange surrounds the package body.

According to a further preferred embodiment, the package comprises aclosure element, which covers the package body at least in part.Preferably, the closure element covers the package body entirely.

According to a further preferred embodiment, the closure element isarranged on the flange, provided on the side walls. The closure elementcould be a foil or a dimensionally stable element. The closure elementcould preferably be connected to the flange by a clamping connection, asnap connection, a welded connection or an adhesion bond, or similarconnections. Preferably, before the usage, such a connection is tornoff, preferably before the usage in order to expose the pre-fillablesyringe in the package body.

According to a further preferred embodiment, the closure element isslidably arranged on the package body. Preferably, the closure elementis slidable along a slide direction, which is preferably oriented alongthe longitudinal direction (X). Advantageously, the closure element isprovided with a guidance element, which extends along the slidedirection, in particular the longitudinal direction (X) on each edge,extending in the direction of the closure element. Preferably, eachflange of the two sidewalls extending in the slide direction, inparticular the longitudinal direction, is received in a guidanceelement.

According to a further preferred embodiment, the package may consist ofplastic. Preferably, the package is produced in an injection moldingprocess, preferably in a multi-component injection molding process.

The object is also addressed by a package suitable and intended forreceiving a pre-fillable syringe comprising a syringe barrel and asyringe tip, wherein the syringe tip is provided with a tip cap, whereinthe package is suitable and intended for receiving a replacement cap forthe pre-fillable syringe.

The package may comprise the single features or combinations of thefeatures described above for the system. Also, the system may comprisethe single features or combinations of the features described for thepackage. Further, the same advantages may apply for the package asdescribed above for the system.

According to a preferred embodiment, the package comprises a packagebody, forming a first cavity defined by a sidewall and a bottom wall.Preferably, the pre-fillable syringe is arranged in said first cavity.Advantageously, at least one second receiving element is provided in thefirst cavity of the package body, in which the syringe barrel isreceived.

According to a further preferred embodiment a distal end of the syringebarrel may be supported by a first of the second receiving elements anda proximal end of the syringe barrel may be supported by a second of thesecond receiving elements. It is advantageous that a first of the secondreceiving elements may be located close to or at the region where thesyringe barrel merges into the syringe tip. Further, it is preferredthat the second of the second receiving elements may be located close tothe finger flange of the syringe arranged in the package body.Preferably the first and the second of the second receiving elements areseparated along the longitudinal axis (X′) of the pre-fillable syringe.Thus, in a state where the pre-fillable syringe is arranged in thepackage body and the syringe barrel is received by the preferably twosecond receiving elements, a central axis of the pre-fillable syringeextends preferably parallel to the bottom wall of the package body.Advantageously, the central axis extends in a height L2 above the bottomwall of the package body.

According to a preferred embodiment, a first receiving element isprovided in the first cavity of the package body. Preferably, thereplacement cap is received in the first receiving element, such thatthe replacement cap is oriented along a vertical axis (Z) of the packagebody and an opening area of the replacement cap is oriented parallel tothe bottom wall of the package body. Preferably, the foot portion of thereplacement cap is received in the first receiving element. Preferably abearing area of the replacement cap contacts the bottom wall of thepackage body.

The object is also addressed by a replacement cap for a pre-fillablesyringe, wherein the replacement cap comprises an inner cap for anengagement with the syringe tip, an outer collar engaging with thesyringe barrel for mounting the replacement cap on the syringe barreland a foot portion replacement cap comprising a foot portion, which issuitable to provide a stable upright positioning of the syringe with thereplacement cap on a surface.

The replacement cap may comprise the single features or combinations ofthe features described above for the system. Also, the system maycomprise the single features or combinations of the features describedfor the replacement cap. Further, the same advantages may apply for thereplacement cap as described above for the system.

The inner cap is preferably arranged on the foot portion of thereplacement cap. Advantageously, the inner cap may consist at leastpartially of an elastomeric material, such that a sealing connectionwith the syringe tip is possible. The syringe tip may preferably beintroduced in the inner cap through an opening of the inner cap.

The outer collar is advantageously formed as a ring which is arrangedalong a vertical axis (Z′) above the opening of the inner cap. The ringis preferably supported by struts which are arranged at the foot portionand surround the inner cap radially. Preferably, the three struts areplaced along the circumference of the ring with an equal distance toeach other. The struts project from the ring radially inward and abut atthe syringe barrel, when the replacement cap is placed on thepre-fillable syringe.

Preferably, the opening area of the replacement cap is defined by thering and the opening of the inner cap, which is placed along thevertical axis (Z) underneath the opening of the ring. The opening of thering and the opening are advantageously parallel to each other and sharethe same central axis. Preferably, the opening area of the replacementcap is defined by the ring. The opening area of the replacement cap,which is defined by the ring, and an opening area of the inner cap arepreferably oriented parallel to the bottom wall of the package body.

According to a preferred embodiment, the foot portion is suitable toprovide a stable upright positioning of the pre-fillable syringe withthe replacement cap on a surface. For a user, an up-right positioningrepresents a very handy, practical way to place the syringe. An uprightpositioning can mean a positioning of the distal end on a supportingsurface, such that the proximal end, equipped with the finger flange andthe rod, is easy to grasp.

Preferably, the foot portion comprises an edge, surrounding a centeraxis of the replacement cap. This edge may be considered as theabove-mentioned tilting edge. The edge defines the shape of the footsection, which can be arbitrary. Preferably, the foot portion has adisc-like shape. Advantageously, the foot portion has a disc-like shape.Preferably, the foot portion has an essentially circular base area.Preferably, the foot portion has a base area which is essentiallyrectangular. Preferably, the distance between the edge and the centeraxis is at least twice the radius of the syringe barrel, more preferablythe distance between the edge and the center axis is at least threetimes the radius of the syringe barrel. Preferably, the distance betweenthe edge and the center axis is at least four times the radius of thesyringe barrel. Preferably, the distance between the edge and the centeraxis is at least five times the radius of the syringe barrel. Due tosuch an embodiment, the tilting edge is further away from the centeraxis. Thus, a larger displacement of the center of gravity is possiblebefore the up-right standing syringe topples. Hence, the standingstability is enhanced.

After the described equipping of the syringe with a replacement cap,which may be done only one-handed, due to the preferable placement andorientation of the replacement cap in the package, the syringe may beplaced upright standing and is easily accessible for the user, whenneeded.

According to a preferred embodiment, the bearing area and/or the edgesurrounding the bearing face is/are coated at least partially with arubberized material. Such an embodiment bears the advantage thatslipping of the foot portion on the supporting surface is inhibited.

According to a preferred embodiment, the foot portion is designed as asuction cup. A suction cup is a device or object that uses the negativefluid pressure of air to adhere to nonporous surfaces, creating apartial vacuum. The working face of the foot portion is preferably madeof elastic, flexible material and has a curved surface. When the centerof the foot portion is pressed against a flat supporting surface, thevolume of the space between the foot portion and the flat surface isreduced. Thus, the air or water between the foot portion and thesur-face is to be expelled past the edge of the cup. By this, a lack ofpressure develops between the foot portion and the supporting surface.The pressure difference between the atmosphere on the outside of thefoot portion and the low-pressure between the foot portion and thesupporting surface keeps the foot portion adhered to the surface.

Preferably, the replacement cap may consist of a plastics material.Preferably the replacement cap is produced by injection molding,preferably by multi-component injection molding.

The object is also addressed by a use of a system according to any ofthe above-mentioned embodiments, comprising the following steps,

-   -   a) retrieving the pre-fillable syringe from the package;    -   b) removing the tip cap from the syringe tip;    -   c) placing the syringe tip in the replacement cap, which is        arranged in the package; and    -   d) retrieving the pre-fillable syringe with the replacement cap        attached to it from the package.

The use of the system may comprise the single features or combinationsof the features described above for the system or package. Also, thesystem or the package may comprise the single features or combinationsof the features described above for the use. Further, the sameadvantages may apply for the use of the system as described above forthe system or the package.

According to a preferred embodiment, the use comprises the step to setthe dosage of the pre-fillable syringe.

According to a preferred embodiment, the usage may also comprise thestep of removing the closure element.

According to a preferred embodiment, the syringe may be placed in anupright position on a support surface after the retrieval of the syringeequipped with the replacement cap of the package. Preferably, a footportion of the replacement cap is suitable to provide a stable uprightpositioning of the pre-fillable syringe with the replacement cap on thesupport surface. Preferably, a bearing area of a foot portion of thereplacement cap contacts the support surface.

In the following, the longitudinal axis (X), horizontal axis (Y), andvertical axis (Z) are used in relation to the package body (3). Thelongitudinal axis (X′), horizontal axis (Y′), and vertical axis (Z′) areused in relation to the pre-fillable syringe (100). The longitudinalaxis (X″), the horizontal axis (Y″), and the vertical axis (Z″) are usedin relation to the replacement cap (300).

In FIGS. 1, 2 a, 3, 4, and 5 a, a pre-fillable syringe is displayed. Apre-fillable syringe (100) comprises a syringe barrel (101) and asyringe tip (102). The syringe barrel (101) is cylindrically shaped andopen at its proximal end. At its distal end, the syringe barrel (101)merges along the distal direction (X′1) into the syringe tip (102). Thesyringe tip (102) may have the form of a cone. Advantageously, thesyringe tip (102) is a Luer-cone. Although not necessarily preferred, itis also conceivable that a piercing means, in particular a needle, acanula, or a similar means, is arranged in the syringe tip (102). In thesyringe barrel (101), the medium to administer is stored. On itsproximal end, the syringe barrel (101) is closed with a plunger or apiston 500, such as shown in FIGS. 9a-9e , which is movable in thesyringe barrel (101).

In a preferred embodiment, the plunger 500, as shown in FIGS. 9a -9 e,can have a flat surface on the bottom 502 thereof instead of a conicsection as in a standard plunger, for instance. More preferably, theplunger 500 can be fully coated with Teflon, even more preferably with afilm of polytetrafluoroethylene (PTFE).

With standard plunger stoppers and siliconized barrels theBreak-Loose-Force (BLF) of the plunger stopper can increase whilestorage duration of the filled syringe. The Glide-Force (GF) may not seethis increase while in storage. Therefore, the difference between thetwo (2) forces (ΔF) can increase over storage duration. This can lead tothe following user-experience after storage: the user increases thepush-force onto a plunger rod until the plunger stopper moves. With arelatively high difference between Break-Loose-Force & Glide-Force, theuser may not able to stop the force quick enough to be able to set asmall dose difference.

Furthermore, the coating favors an easiest actuation of the device andlowest level of subvisible particulates.

The plunger or the piston (e.g., as in FIGS. 9a-9e ) can be attached toa rod (104), which projects in the proximal direction (X′2) from thesyringe barrel (101). On the proximal end of the rod (104), a fingersupport (109) is arranged. Further, the syringe barrel (101) is providedwith a finger flange (105). In the present case, the finger flange (105)is a clip-on-finger flange. which may be clipped on a finger flange onthe syringe barrel (101). Such clip-on-finger flanges bear the advantageof a larger area to grasp for the user.

The pre-fillable syringe (100) is provided with a tip cap (103) which isarranged on the syringe tip (102). The tip cap (103) may consist atleast in part of an elastomeric material.

In FIGS. 2b and 5b , a replacement cap (300) is depicted. In FIGS. 3, 4and 8, a pre-fillable syringe (100) is depicted, which is equipped witha replacement cap (300). In FIGS. 7, 8 and 10, a package (1) is shown,in which a replacement cap (300) is arranged.

The replacement cap (300) comprises an inner cap (301) for an engagementwith the syringe tip (102). The inner cap (301) is arranged on a footportion (303) of the replacement cap. Preferably, the inner cap (301)may consist at least partially of an elastomeric material, such that asealing connection to the syringe tip (102) is possible. The syringe tip(102) may be introduced in the inner cap (301) through the opening (304)of the inner cap (301).

Further, the replacement cap (300) comprises an outer collar (302)engaging with the syringe barrel (101) for mounting the replacement cap(300) and a foot portion (303).

The outer collar (300) comprises a ring (305) which is arranged alongthe longitudinal axis (X″) above the opening (304) of the inner cap(301). The ring (305) is supported by struts (306). Preferably, threestruts (306) are placed along the circumference of the ring (305) withan equal radial distance to each other. The struts (306) are arranged atthe foot portion (303) and surround the inner cap (301) radially.Further, the struts (306) project from the ring (305) radially inwardand abut at the syringe barrel (101), when the replacement cap (300) isplaced on the pre-fillable syringe (100).

The replacement cap (300) comprises an opening (309) and an opening area(309 a), which is defined by the ring (305). The opening (304) of theinner cap (301) is placed along the longitudinal axis (X″) underneaththe ring opening (309). Thus, the opening area (309 a) is orientedparallel to an opening area of the opening (304) of the inner cap (301).The pre-fillable syringe (100) is introduced first through the opening(309) and then into the opening (304) of the inner cap (301). Theopening (309) and the opening (304) share the same center axis (307). InFIGS. 7 and 8, a package (1) is shown, in which a replacement cap (300)is arranged. The opening area (309 a) is then oriented parallel to thebottom wall (6) of the package body (3).

The foot portion (303) is suitable to provide a stable uprightpositioning of the pre-fillable syringe (100) on a support surface(400). This is depicted in FIG. 4. Under an upright positioning apositioning of the distal end of the pre-fillable syringe (100) on asupport surface (400) is understood, such that the proximal end of thepre-fillable syringe (100), which is equipped with the finger flange(105) and the rod (104), is easy to grasp. The foot portion (303)comprises a bearing area (311), which contacts the supporting surface(400). The bearing area (311) may stretch over a part of a distal endface (312) of the replacement cap (300), which constitutes the distalend of the foot portion. It is also conceivable that the bearing area(311) stretches of the entire distal end face (312). Further, it isconceivable that the bearing area (311) stretches along the edge of thedistal end face (312).

The pre-fillable syringe (100) has an extension which is by far largeralong the longitudinal axis (X′) than along the horizontal axis (Y′). Astable positioning is possible as long as the center of gravity iswithin an area defined by an edge of the bearing area (311). Adisplacement of the center of gravity in a radial direction (along thehorizontal axis (Y′) or the vertical axis (Z′)) may not affect thestability of the standing as long as the center of gravity is notfurther radially outwards placed than the tilting edge. Due to theprovision of a finger flange (105) at the proximal end of thepre-fillable syringe (100), the center of gravity is closer to theproximal end of the pre-fillable syringe (100). This means that a smalldisplacement of the center of gravity causes the upright standingsyringe to topple.

The bearing area (311) comprises an edge (313) which surrounds a centeraxis (307) of the replacement cap (300) at an edge-distance (308). Theedge-distance (308) is at least twice the radius (112) of the syringebarrel (101), more preferably the edge-distance (308) is at least threetimes the radius (112) of the syringe barrel (101). Preferably, theedge-distance (308) is at least four times the radius (112) of thesyringe barrel (101). Preferably, the edge-distance (308) is at leastfive times the radius (112) of the syringe barrel (101). Due to such anembodiment, the tilting edge is further away from the center axis. It istherefore a larger displacement necessary to tip the pre-fillablesyringe (100) over.

The distal end face (312) of the foot portion (303) comprises an edge.The edge of the distal end face (312) and the edge (313) of the bearingarea (311) are parallel to each other and adjacent.

In the FIGS. 2b , 3, 4, 7, and 8, the replacement cap (300) has adisc-like shape which is essentially circular, except for a cut portion(314). Said edge distance (308) is therefore essentially the radius ofthe disc-like shaped foot portion (313). The cut portion (314) extendsalong a secant line, meaning a line that intersects the circularreplacement cap on two points of the diameter, wherein the secant doesnot run through the center of the circular replacement cap. The cutportion (314) is adjacent to a sidewall (5) extending along thelongitudinal axis (X).

The foot portion (303) according an embodiment of FIG. 5b isrectangular. The edge-distance (308) would therefore be the distance tothe edge closest to the center axis (307).

The foot portion (303) is, due to its dimension, also a suitable gripportion for the user to grasp the replacement cap (300). The footportion (303) may also be designed as a suction cup, which is a deviceor object that uses the negative fluid pressure of air to adhere tononporous surfaces, creating a partial vacuum.

In the FIGS. 6 to 8, a package (1) and/or a system (200) are depicted.The system (200) comprises a pre-fillable syringe (100) with a syringebarrel (101) and a syringe tip (102) and a package (1) suitable andintended for receiving the pre-fillable syringe (100), wherein thesyringe tip (102) is provided with a tip cap (103), wherein the system(200) comprises a replacement cap (300) for the pre-fillable syringe(100), and wherein the package (1) is suitable and intended forreceiving the replacement cap (300).

The package (1) suitable and intended for receiving a pre-fillablesyringe (100) comprises a syringe barrel (101) and a syringe tip (102),wherein the syringe tip (102) is provided with a tip cap (103), whereinthe package (1) is suitable and intended for receiving a replacement cap(300) for the pre-fillable syringe (100).

The package (1) comprises a package body (3), forming a first cavity(4), defined by a sidewall (5) and a bottom wall (6), wherein thepre-fillable syringe (100) is arrangeable or arranged in said firstcavity (4). The package body (3) extends along a longitudinal axis (X),a horizontal axis (Y), and a vertical axis (Z), which are perpendicularto each other. Further, the package body (3) has a rectangular shape.

At least one second receiving element (7, 7 a, 7 b) is provided in thefirst cavity (4) of the package body (3), in which the syringe barrel(101) is receivable. The embodiments shown in the figures have twosecond receiving elements (7, 7 a, 7 b), which are arranged at thebottom wall (6) of the package body (3).

The first (7 a) of the second receiving elements (7) comprise asemicircular top section (26) arranged on a base section (27). Thesemicircular top section (26) is dimensioned to receive the syringebarrel (101). According the embodiments in FIGS. 6 to 8, the second (7b) of the second receiving elements (7) also comprises a semicirculartop section (26) arranged on a base section (27).

A distal end (101 a) of the syringe barrel (101) is supported by a first(7 a) of the second receiving elements (7), and a proximal end (101 b)of the syringe barrel (101) is supported by a second (7 b) of the secondreceiving elements (7).

In case the pre-fillable syringe (100) is arranged in the package (1),the first (7 a) of the second receiving elements (7) is located close toor at the region (110), where the syringe barrel (101) merges into thesyringe tip (102). Further, the second (7 b) of the second receivingelements (7) is located close to the finger flange (105) of thepre-fillable syringe (100) arranged in the package body (3).

The first cavity (4) of the package body (3) is provided with a thirdreceiving element (8), in which the rod (104) of the pre-fillablesyringe (100) is receivable or received. The third receiving element (8)comprises two walls (8 a, 8 b) extending along the vertical axis (Z),forming a cavity in which the rod (105) is receivable or received.Further, the third receiving element (8) has a bottom wall, formedsemicircularly, and connecting the walls (8 a, 8 b). The third receivingelement (8) ends at its proximal end in a fixture element (30), in whichthe finger support (109) of the rod (104) is received.

Between the second of the second receiving elements (7, 7 b) and thethird receiving element (8), a gap (29) is formed. Through this gap(29), the finger flange (105) of the pre-fillable syringe (100) mayproject, when the pre-fillable syringe (100) is placed inside thepackage body (3). Thus, the finger flange (105) is sandwiched betweenthe second (7 b) of the second receiving elements (7) and the thirdreceiving element (8), such that the pre-fillable syringe (100) isfastened in the package body (3).

The third receiving element (8) stretches, after the gap (29),essentially along the length of the section of the rod (104) projectingfrom the syringe barrel (101).

When the pre-fillable syringe (100) is placed in the package body (3),it is supported by the first (7 a) of the second receiving elements (7),preferably by the second (7 b) of the second receiving elements (7), andpreferably by the third receiving element (8), in particular by thefixture element (30). Thus, in a state where the pre-fillable syringe(100) is in the package body (3), a central axis (111) of thepre-fillable syringe (100) extends parallel to the bottom wall (6) ofthe package body (3). The central axis (111) extends in a height L2above the bottom wall (6) of the package body (3). The height L2 allowsan easy grasping of the pre-fillable syringe (100).

The replacement cap (300) is arranged in the package (1), such that anopening (309) of the replacement cap (300) is oriented along a verticalaxis (Z) of the package body (3). An opening area (309 a) of thereplacement cap (300) is oriented parallel to the bottom wall (6) of thepackage body (3). Preferably the center axis (307) of the replacementcap (300) is parallel to the height extension of the sidewalls (5) ofthe package body (3).

The side wall(s) (5) of the package body (3) surround the package body(3) along the longitudinal axis (X) and the horizontal axis (Y). Thesidewall(s) (5) extend(s) along the vertical axis (Z) with a height L4.The height L4 is at least the height L2 plus the radius (112) of thesyringe barrel (101). The upper (along the vertical axis (Z)) end of theside wall(s) (5) is provided with a flange (31). The flange (31) extendsoutwards and surrounds the package body (3) along the longitudinal axis(X) and the horizontal axis (Y), preferably without any gap.

On the flange (31), a closure element (15) may be arranged. Preferablythe closure element is connected with a suitable connection to theflange (31). The closure element (15) is shown only partly in FIG. 6 andmay be a foil or a slidable stable element.

According to the embodiment of FIGS. 6 to 8, the first cavity (4) of thepackage body (3) is provided with a first receiving element (2), inwhich the replacement cap (300) is received. In particular, wherein thefoot portion (303) of the replacement cap (300) is received in the firstreceiving element (2). The first receiving element (2) thereforeessentially is the shape of the outer perimeter of the foot portion(303). In case of the FIGS. 6 to 8 this shape would be essentiallycircular with a cut portion extending along a secant.

The first receiving element (2) comprises a sidewall (12), which isarranged on the bottom wall (6) of the package body (3). This sidewall(12) and the sidewall (5) of the package body (3) define a cavity, whichcomplies with the shape of the foot portion (303) of the replacement cap(300). In the present case of FIGS. 6 to 8, this cavity and the footportion (303) of the replacement cap (300) are shaped essentiallycircularly. The bearing surface (311) of the replacement cap (300) sitstherefore on the bottom wall (6) of the package body (3), such that thereplacement cap (300) is arranged in the package (1), such that anopening (309) of the replacement cap (300) is oriented along a verticalaxis (Z) of the package body (3). An opening area (309 a) of thereplacement cap (300) is oriented parallel to the bottom wall (6) of thepackage body (3).

The height (13) of the sidewall (12) along the vertical axis (Z) isessentially the height (310) of the replacement cap (300) at its outeredge.

In the FIGS. 1 to 8, also a use of the system (200) is displayed. Theuse comprises preferably removing the closure element from the packagebody (3). The pre-fillable syringe (100) is then retrieved from thepackage (1). Then, the tip cap (103) is removed. Optionally, the dosageof the pre-fillable syringe is set. Then, the replacement cap (300) ismounted on the pre-fillable syringe (100). For this, the syringe tip(102) is placed in the replacement cap (300) which is arranged in thepackage (1). The syringe tip (102) is let through the opening (309) ofthe replacement cap (300) and the opening (304) of the inner cap (301).Eventually, the inner cap (301) is attached to the syringe tip (102) andthe ring (305) or the struts (306) abut on the syringe barrel (101).During the mounting, the replacement cap (300) is still inside thepackage (1). Since the opening (309) of the replacement cap (300) isoriented along the vertical axis (Z) of the package body (3), thesyringe tip (102) may easily be introduced into the replacement cap(300). The handling of the syringe (100) is therefore possible usingonly one hand. It is not necessary to put the pre-fillable syringe (100)down to obtain or align the replacement cap (300) relative to thepre-fillable syringe (100). The pre-fillable syringe (100) with thereplacement cap (300) attached to it may then be retrieved from thepackage (1).

The pre-fillable syringe (100) may preferably be placed in an uprightposition on a support surface (400). Preferably, a foot portion (303) ofthe replacement cap (300) is suitable to provide a stable uprightpositioning of the pre-fillable syringe (100) with the replacement cap(300) on the support surface (400), wherein a bearing area (311) of afoot portion (303) of the replacement cap (300) contacts the supportsurface (400).

Such a system (200) has the advantage that a package (1) is presented tothe user which comprises the pre-fillable syringe (100) to use and asuitable replacement cap (300). The replacement cap (300) is alreadyavailable to the user and does not need to be obtained otherwise.Further, the replacement cap (300) does not need to be retrieved from anadditional package.

The invention is also directed to the system herein disclosed, whereinthe syringe is pre-filled with a ready-to-use pharmaceuticalformulation.

Advantageously, the pharmaceutical formulation is in form of solution oremulsion and comprises one or more active ingredients suitable for oral,intramuscular or intravenous administration.

More advantageously, the formulation is an aqueous solution or ahydroalcoholic solution.

Preferably, the pharmaceutical formulation is an aqueous solution or ahydroalcoholic solution comprising buprenorphine, for an efficacioustreatment by sublingual and/or buccal administration of patientsaffected by opiate withdrawal syndrome (OWS), more preferably neonatesaffected by neonatal OWS.

More preferably, the buprenorphine formulation in form of aqueoussolution comprises:

-   -   i) from 0.005 to 0.02% w/v of buprenorphine or a        pharmaceutically acceptable salt thereof as the sole active        ingredient;    -   ii) from 0.5% to 10% w/v of a thickening agent; and    -   iii) a buffering agent in an amount to provide a pH of 5.0-7.0.

Buprenorphine shall be utilized as a base or in the form of apharmaceutically acceptable salt formed with an inorganic or organicacid, such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid,pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid,malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid,palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid,hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid,methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

Preferably, buprenorphine is present as the hydrochloride salt.

Advantageously, the concentration of buprenorphine, expressed as freebase, shall be comprised between 0.005 and 0.02% w/v, preferably between0.006 and 0.01% w/v, expressed as free base.

In a particular embodiment, the concentration of buprenorphinehydrochloride is 0.0075% w/v, expressed as free base. The concentrationof the thickening agent shall be comprised between 0.5% and 10%, w/v,preferably between 0.6% and 8.0% w/v. The type and amount of thethickening agent shall be properly selected to achieve an adequateviscosity to retain the formulation as much as possible under the tongueof the patient, to minimize the absorption through the gastrointestinaltract.

At the same time, the viscosity should be not too high to retard therelease of the active ingredient from the matrix and hence, its localabsorption.

More preferably, the concentration of the thickening agent may bebetween 1.0 and 6.0% w/v.

In particular embodiments, said concentration is 1.0% w/v, or 1.5% w/v,or 2.0% w/v, or 6.0% w/v.

Advantageously, the thickening agent may be selected from water-solublepolysaccharides such as alginates, carrageenans, pectin, water-solublederivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses andhydroxyalkylalkylcelluloses, such as methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose,hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcelluloseesters such as cellulose acetate phthalate (CAP),hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses,carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such ascarboxymethylcellulose and their alkali metal salts; water-solublesynthetic polymers such as polyacrylic acids and polyacrylic acidesters, polymethacrylic acids and polymethacrylic acid esters,polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP),polyvinylpyrrolidone (PVP) and polycrotonic acids; also suitable arephthalated gelatin, gelatin succinate, crosslinked gelatin, shellac,water-soluble chemical derivatives of starch, cationically modifiedacrylates and methacrylates possessing, for example, a tertiary orquaternary amino group, such as the diethylaminoethyl group, which maybe quaternized if desired.

Preferably, the thickening agent is a water-soluble cellulose derivativeselected from group consisting of hydroxyethylcellulose (HEC) or analkali metal salt of carboxymethylcellulose (CMC) such as the sodiumsalt.

In fact, the thickening agents belonging to said classes may provide thesuitable viscosity, while with other agents of the class of gums, suchas xanthan gum, the viscosity of the formulation turned out to be toohigh.

Advantageously, the viscosity of the formulation at 25±2° C. shall becomprised between 500 and 2300 mPas (1 mPas corresponds to 1centipoise), preferably between 700 and 2100 mPas The viscosity may bedetermined by any known method, for example using a rheometer.

Advantageously, the pH of the formulation of the invention may becomprised between 5.0 and 7.0, more advantageously between 5.2 and 6.8,preferably between 5.5 and 6.5.

When a water soluble cellulose derivative is used, preferredformulations have a pH between 5.5 and 6.5 and an amount of thickeningagent comprised between 1.0% and 2.0% w/v, even more preferably of 1.5%w/v. The preferred thickening agent of this class may behydroxyethylcellulose. Said excipient is commercially available asNatrosol 250 HX™.

Any buffering agent able of providing the pH maybe used, for examplephosphate or citrate buffers as sodium or potassium salts. The skilledperson in the art shall determine the proper amount.

In a preferred embodiment, anhydrous citric acid and sodium citrateanhydrous is used as buffering agent.

Said formulation may also contain other excipients such as flavoringagents and/or sweeteners.

Flavoring agents may be chosen from natural and synthetic flavoringliquids. An illustrative list of such agents includes volatile oils,synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins orextracts derived from plants, leaves, flowers, fruits, stems andcombinations thereof. A representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alpha-citral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof; saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,xylitol, and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener

3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof. Other sweeteners may also be used. ypically, the skilledperson in art shall select the sweetener and/or flavoring agent amongthose considered safe for neonatal administration.

Said formulation may also contain permeation enhancers such as propyleneglycol, and polyoxyl hydrogenated castor oil derivatives, for examplepolyoxyl 40 hydrogenated castor oil (commercially available as KolliphorRH 40™).

In preferred embodiment, the formulation has the following composition:0.05-0.01% w/v buprenorphine hydrochloride expressed as a base, 1.5% w/vhydroxyethylcellulose, 0.12% w/v anhydrous citric acid, 1.13% w/v sodiumcitrate anhydrous, water for injection, and its pH is of 6.0±0.3.

In an alternative embodiment, the formulation may have the followingcomposition: 0.05-0.01% w/v buprenorphine hydrochloride expressed as abase, 6.0% w/v sodium carboxymethylcellulose, 0.12% w/v anhydrous citricacid, 1.13% w/v sodium citrate anhydrous, water for injection, and itspH is of 6.0±0.3.

More details are reported in the International PCT patent applicationno. PCT/EP2018/078447 and U.S. application Ser. No. 16/164,282, theentire content of each of which is incorporated herein by reference.

The pharmaceutical formulations can be prepared according to knownmethods.

In a preferred embodiment, the pharmaceutical formulation is sterile andpre-filling is carried out under aseptic conditions is carried outaccording to methods known in the art.

Even though it less preferred, the pharmaceutical formulation can be inform of a dry powder to be dissolved extemporaneously before use.

Therefore, the invention is also directed to a kit comprising the systemherein disclosed together with a pharmaceutical formulation in form ofeither ready-to-use aqueous solution or powder to be reconstituted in asuitable vehicle, and instructions to administer said pharmaceuticalformulation.

1. A system comprising a pre-tillable syringe with a syringe barrel anda syringe tip and a package suitable and intended for receiving thepre-1illable syringe, wherein the syringe tip is provided with a tipcap, characterized in that the system comprises a replacement cap forthe pre-fillable syringe, wherein the package is suitable and intendedfor receiving the replacement cap.
 2. The system according to claim 1,characterized in that the package comprises a package body forming afirst cavity, defined by a sidewall and a bottom wall, wherein thepre-fillable syringe is arranged in said first cavity, wherein at leastone second receiving element is provided in the first cavity of thepackage body, in which the syringe barrel is received, wherein a distalend of the syringe barrel is supported by a first of the secondreceiving elements and as proximal end of the syringe barrel issupported by a second of the second receiving elements.
 3. The systemaccording to claim 1, characterized in that the replacement cap isarranged in the package, such that an opening of the replacement cap isoriented along a vertical axis of the package body, wherein an openingarea of the replacement cap is oriented parallel to the bottom wall ofthe package body.
 4. The system according to claim 1, characterized inthat at least one third receiving element is provided in the firstcavity of the package body, in which a rod of the pre-fillable syringeis received wherein a gap between the second the second receivingelements and the third receiving element is provided, wherein a fingerflange of the pre-fillable syringe projects through said gap such thatthe finger flange is sandwiched between second of the second receivingelements and the third receiving element.
 5. The system according toclaim 1, characterized in that the replacement cap comprises an innercap for an engagement with the syringe tip, an outer collar engagingwith the syringe barrel for mounting the replacement cap on the syringebarrel and a foot portion,
 6. The system according to claim 2,characterized in that a first receiving element is provided in the firstcavity of the package body, wherein the replacement cap is received inthe first receiving element wherein the foot portion of the replacementcap is received in the first receiving element,
 7. The system accordingto claim 5, characterized in that the foot portion is suitable toprovide a stable upright positioning of the pre-fillable syringe withthe replacement cap on a support surface, wherein the foot portioncomprises a bearing area, which contacts the support surface, whereinthe bearing area comprises an edge, which surrounds a center axis of thereplacement cap at an edge-distance, wherein the edge-distance is atleast twice the radius of the syringe barrel, wherein the foot portionhas a disc-like shape.
 8. The system according to claim 2, characterizedin that the sidewall of the package body is provided with a flange onits upper end, wherein the package comprises a closure element, whichcovers the package body at least in part, wherein the closure element isarranged on the flange.
 9. A package suitable and intended for receivinga pre-fillable syringe comprising a syringe barrel and a syringe tip,wherein the syringe tip is provided with a tip cap, characterized inthat the package is suitable and intended for receiving a replacementcap for the pre-fillable syringe.
 10. The package according to claim 9,characterized in that the package comprises a package body forming afirst cavity, defined by a sidewall and a bottom wall wherein thepre-fillable syringe is arranged in said first cavity, wherein at leastone second receiving element is provided in the first cavity of thepackage both, in which the syringe barrel is received.
 11. The packageaccording to claim 10, characterized in that a first receiving elementis provided in the first cavity of the package body, wherein thereplacement cap is received in the first receiving element, such thatthe replacement cap is oriented along a vertical axis of the packagebody and an opening area of the replacement cap is oriented parallel tothe bottom wall of the package body, wherein the foot portion of thereplacement cap is received in the first receiving element.
 12. Thepackage according to claim 10, characterized in that at least one thirdreceiving element is provided in the first cavity of the package body,in which a rod of the pre-fillable syringe is receivable, wherein a gapbetween the second of the second receiving elements and the thirdreceiving element is provided, wherein a finger flange of thepre-fillable syringe may project through said gap such that the fingerflange is sandwiched between second of the second receiving elements andthe third receiving element.
 13. A replacement cap for a pre-fillablesyringe, characterized in that the replacement cap comprises an innercap for an engagement with the syringe tip, an outer collar engagingwith the syringe barrel for mounting the replacement cap on the syringebarrel and a foot portion, which is suitable to provide a stable uprightpositioning of the pre-fillable syringe with the replacement cap on asupport surface.
 14. The replacement cap according to claim 13,characterized in that the foot portion comprises a bearing area, whichcontacts the support surface, wherein the bearing area comprises anedge, which surrounds a center axis of the replacement cap at anedge-distance, wherein the edge-distance is at least twice the radius ofthe syringe barrel, wherein the foot portion has a disc-like shape. 15.Use of the system according to claim 1, comprising the following steps:a) retrieving the pre-tillable syringe from the package; b) removing thetip cap from the syringe tip; c) placing the syringe tip in thereplacement cap, which is arranged in the package; and d) retrieving thepre-tillable syringe with the replacement cap attached to it from thepackage.
 16. The system according to claim 1, wherein the syringe ispre-filled with a ready-to-use pharmaceutical formulation.
 17. Thesystem according to claim 16, wherein the pharmaceutical formulation isin form of solution or emulsion and comprises one or more activeingredients suitable for oral, intramuscular or intravenousadministration.
 18. The system according to claim 16, wherein theformulation is an aqueous solution, or a hydroalcoholic solution. 19.The system according to claim 16, wherein the pharmaceutical formulationis an aqueous solution or a hydroalcoholic solution for sublingualand/or buccal administration comprising buprenorphine as activeingredient.
 20. A kit comprising the system according to claim 1,together with a pharmaceutical formulation in form of eitherready-to-use aqueous solution or powder to be reconstituted in asuitable vehicle, and instructions to administer said pharmaceuticalformulation.